Pulmonary tuberculosis (TB) is a significant public health problem both in the United States, and worldwide. More recently, multi-drug resistant TB (MDR-TB) has emerged as a new infectious disease threat. In the absence of effective antibiotic therapy, there is a need to develop therapeutic approaches to augment host immunity against MDR-TB bacilli. Protective immunity against Mycobacterium tuberculosis (Mtb), the bacterium responsible for pulmonary TB, is conferred by both innate and adaptive immune mechanisms. Control of Mtb growth is initially conferred by innate immune cells, such as alveolar macrophages, which also serve as the host cells for this intracellular pathogen. By themselves, these innate immune mechanisms cannot eradicate the infection. Antigen-specific adaptive immune responses, predominantly conferred by gamma interferon (IFN)-secreting CD4+ T cells, are necessary for a protective host response. Toll-like receptor (TLR) proteins are pattern recognition receptors that recognize a variety of mycobacterial products. Engagement of TLR proteins activates variety of innate immune responses. In addition, TLR function is necessary for the maturation and activation of dendritic cells. Dendritic cells are crucial to the initiation of adaptive immune responses because of their ability to process and present bacterial antigens to na'fve T cells. We recently observed that both TLR2 and TLR4 participate in the host responses against mycobacterial infection. Furthermore, these TLR proteins appear to regulate different aspects of the host response. TLR2 appears to be necessary for the activation of innate immune responses, whereas TLR4 appears to regulate the polarization of naive antigen-specific T helper precursor (Thp) cells towards an IFNg- producing Thl phenotype. Our specific aims will determine (1) whether TLR2-/- mice fail to develop antigen-specific T cells because of an intrinsic defect in the maturation and/or activation of dendritic cells, and (2) whether antigen-specific CD4+ T cells from TLR4-/- mice fail to secrete gamma IFN because of an intrinsic defect in commitment of Thp cells to a Th1 phenotype.